Aminopeptidase-N/CD13 (EC 3.4.11.2) inhibitors: Chemistry, biological evaluations, and therapeutic prospects

Abstract

Aminopeptidase N (APN)/CD13 (EC 3.4.11.2) is a transmembrane protease present in a wide variety of human tissues and cell types (endothelial, epithelial, fibroblast, leukocyte). APN/CD13 expression is dysregulated in inflammatory diseases and in cancers (solid and hematologic tumors). APN/CD13 serves as a receptor for coronaviruses. Natural and synthetic inhibitors of APN activity have been characterized. These inhibitors have revealed that APN is able to modulate bioactive peptide responses (pain management, vasopressin release) and to influence immune functions and major biological events (cell proliferation, secretion, invasion, angiogenesis). Therefore, inhibition of APN/CD13 may lead to the development of anti-cancer and anti-inflammatory drugs. This review provides an update on the biological and pharmacological profiles of known natural and synthetic APN inhibitors. Current status on their potential use as therapeutic agents is discussed with regard to toxicity and specificity.

LYP, a novel bestatin derivative, inhibits cell growth and suppresses APN/CD13 activity in human ovarian carcinoma cells more potently than bestatin

“…Since APN/CD13 is expressed in OVCA and is known to stimulate cell proliferation, tumor invasion, and angiogenesis [10], APN/CD13 is considered to be an important target for therapy of OVCA [22][23][24] high levels of APN/CD13 in ES-2 cells correlates with increased malignant behavior, such as cell proliferation, invasive ability, and angiogenesis [7]. Therefore, ES-2 cells have been used to evaluate the efficacy of bestatin and other drugs targeting APN/CD13 [7].…”

Medicinal Chemistry of α‐Hydroxy‐β‐Amino Acids

“…Amastatin and probestatin inhibited AP-A and AP-W in the low micromolar range (1.5-20 mM). Leuhistin inhibited AP-N, AP-A, and AP-B [141]. Thus, the reported data emphasize the need for more specific and targeted aminopeptidase inhibitors.…”

QSAR studies of aminopeptidase N/CD13 (APN) inhibitors with the scaffold 3-phenylpropane-1,2-diamine and molecular docking

“…The highly potent drug Bestatin could only interact with the target partly (Bauvois and Dauzonne, 2006). Figure 5 depicts a schematic of Fig.…”

“…Based on the above findings, a substantial number of natural and synthetic inhibitors of APN are studied for the sake of suppressing various cancers by destroying tumor neovascularization, blocking the growth, metastasis and recurrence of cancer effectively (Bauvois and Dauzonne, 2006). Among them, low molecular weight peptidomimetic derivatives, the structural or functional mimetics of natural active peptides, show great significance and bright prospects with three notable advantages of preserving the bioactivity, improving the bioavailability and the specificity towards the targets for acting as ideal modified replacement of natural peptides (Li and Wenfang, 2009).…”